CN117285413A - Synthesis method of terbutaline key intermediate 3, 5-dihydroxyacetophenone - Google Patents
Synthesis method of terbutaline key intermediate 3, 5-dihydroxyacetophenone Download PDFInfo
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- CN117285413A CN117285413A CN202310995945.0A CN202310995945A CN117285413A CN 117285413 A CN117285413 A CN 117285413A CN 202310995945 A CN202310995945 A CN 202310995945A CN 117285413 A CN117285413 A CN 117285413A
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- Prior art keywords
- dihydroxyacetophenone
- methyl
- terbutaline
- reaction
- key intermediate
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- XWTYSIMOBUGWOL-UHFFFAOYSA-N (+-)-Terbutaline Chemical compound CC(C)(C)NCC(O)C1=CC(O)=CC(O)=C1 XWTYSIMOBUGWOL-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 229960000195 terbutaline Drugs 0.000 title claims abstract description 20
- WQXWIKCZNIGMAP-UHFFFAOYSA-N 3',5'-Dihydroxyacetophenone Chemical compound CC(=O)C1=CC(O)=CC(O)=C1 WQXWIKCZNIGMAP-UHFFFAOYSA-N 0.000 title claims description 21
- 238000001308 synthesis method Methods 0.000 title description 3
- 238000000034 method Methods 0.000 claims abstract description 20
- -1 compound methyl 3, 5-dimethoxybenzoate Chemical class 0.000 claims abstract description 13
- 239000002253 acid Substances 0.000 claims abstract description 12
- 239000002904 solvent Substances 0.000 claims abstract description 12
- UYEMGAFJOZZIFP-UHFFFAOYSA-N 3,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC(O)=C1 UYEMGAFJOZZIFP-UHFFFAOYSA-N 0.000 claims abstract description 8
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims abstract description 8
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims abstract description 8
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000000126 substance Substances 0.000 claims abstract description 8
- 229940126214 compound 3 Drugs 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 7
- 238000002425 crystallisation Methods 0.000 claims abstract description 7
- 230000008025 crystallization Effects 0.000 claims abstract description 7
- YXUIOVUOFQKWDM-UHFFFAOYSA-N Dimethylaether-alpha-resorcylsaeure-methylester Natural products COC(=O)C1=CC(OC)=CC(OC)=C1 YXUIOVUOFQKWDM-UHFFFAOYSA-N 0.000 claims abstract description 6
- 150000004702 methyl esters Chemical class 0.000 claims abstract description 6
- 238000010189 synthetic method Methods 0.000 claims abstract description 6
- 238000006114 decarboxylation reaction Methods 0.000 claims abstract description 5
- 238000010520 demethylation reaction Methods 0.000 claims abstract description 5
- 230000007062 hydrolysis Effects 0.000 claims abstract description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 5
- 238000005580 one pot reaction Methods 0.000 claims abstract description 5
- 239000003513 alkali Substances 0.000 claims abstract description 4
- 238000006482 condensation reaction Methods 0.000 claims abstract description 4
- 239000012535 impurity Substances 0.000 claims abstract description 4
- 239000002994 raw material Substances 0.000 claims abstract description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 3
- 238000005886 esterification reaction Methods 0.000 claims abstract description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 3
- 239000001257 hydrogen Substances 0.000 claims abstract description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 3
- 230000011987 methylation Effects 0.000 claims abstract description 3
- 238000007069 methylation reaction Methods 0.000 claims abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- 239000007810 chemical reaction solvent Substances 0.000 claims description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 3
- 239000002585 base Substances 0.000 claims description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 claims description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 2
- 229940011051 isopropyl acetate Drugs 0.000 claims description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims 9
- 238000009776 industrial production Methods 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 230000017858 demethylation Effects 0.000 abstract description 2
- 230000002349 favourable effect Effects 0.000 abstract description 2
- 238000004064 recycling Methods 0.000 abstract description 2
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 abstract 2
- HEJLFBLJYFSKCE-UHFFFAOYSA-N 2',3'-Dihydroxyacetophenone Chemical compound CC(=O)C1=CC=CC(O)=C1O HEJLFBLJYFSKCE-UHFFFAOYSA-N 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 229920001971 elastomer Polymers 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 229960005105 terbutaline sulfate Drugs 0.000 description 5
- KFVSLSTULZVNPG-UHFFFAOYSA-N terbutaline sulfate Chemical compound [O-]S([O-])(=O)=O.CC(C)(C)[NH2+]CC(O)C1=CC(O)=CC(O)=C1.CC(C)(C)[NH2+]CC(O)C1=CC(O)=CC(O)=C1 KFVSLSTULZVNPG-UHFFFAOYSA-N 0.000 description 5
- 239000000203 mixture Substances 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- QODJHYBESCIPOG-UHFFFAOYSA-N (3-acetyl-5-acetyloxyphenyl) acetate Chemical compound CC(=O)OC1=CC(OC(C)=O)=CC(C(C)=O)=C1 QODJHYBESCIPOG-UHFFFAOYSA-N 0.000 description 2
- WUXKAYZEXYAYIT-UHFFFAOYSA-N 2-bromo-1-(3,5-dihydroxyphenyl)ethanone Chemical compound OC1=CC(O)=CC(C(=O)CBr)=C1 WUXKAYZEXYAYIT-UHFFFAOYSA-N 0.000 description 2
- AUSUKEFQHQUODI-UHFFFAOYSA-N 5-(2-bromo-1-hydroxyethyl)benzene-1,3-diol Chemical compound BrCC(O)C1=CC(=CC(=C1)O)O AUSUKEFQHQUODI-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000005893 bromination reaction Methods 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 102100039705 Beta-2 adrenergic receptor Human genes 0.000 description 1
- 101710152983 Beta-2 adrenergic receptor Proteins 0.000 description 1
- 208000007101 Muscle Cramp Diseases 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 102000016966 beta-2 Adrenergic Receptors Human genes 0.000 description 1
- 108010014499 beta-2 Adrenergic Receptors Proteins 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000000916 dilatatory effect Effects 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000013013 elastic material Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 229960002288 procaterol Drugs 0.000 description 1
- FKNXQNWAXFXVNW-BLLLJJGKSA-N procaterol Chemical compound N1C(=O)C=CC2=C1C(O)=CC=C2[C@@H](O)[C@@H](NC(C)C)CC FKNXQNWAXFXVNW-BLLLJJGKSA-N 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229960002052 salbutamol Drugs 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 238000009423 ventilation Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/673—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by change of size of the carbon skeleton
- C07C45/676—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by change of size of the carbon skeleton by elimination of carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/78—Separation; Purification; Stabilisation; Use of additives
- C07C45/81—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/10—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with ester groups or with a carbon-halogen bond
- C07C67/11—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with ester groups or with a carbon-halogen bond being mineral ester groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Crystallography & Structural Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The scheme belongs to the technical field of pharmaceutical chemical industry, and particularly relates to a synthetic method of a terbutaline key intermediate 3, 5-di-light acetophenone. The method comprises the following steps: step S10, taking 3, 5-dihydroxybenzoic acid SM as a raw material, synchronously carrying out methylation and methyl esterification reaction with dimethyl sulfate under alkaline conditions, and carrying out aftertreatment to obtain a compound methyl 3, 5-dimethoxybenzoate; step S20, carrying out condensation reaction on the compound 3, 5-dimethoxy methyl benzoate and methyl acetate under the action of strong alkali hydrogen drawing to obtain the compound 3- (3, 5-dimethoxy phenyl) -3-oxypropionic acid methyl ester; step S30, under the strong acid condition, the compound B synchronously carries out hydrolysis decarboxylation reaction and demethylation reaction at high temperature by a one-pot method, and then the dihydroxyacetophenone with high purity is obtained by solvent crystallization and impurity removal; the hydrolysis decarboxylation and the demethylation are more favorable for synchronously recycling the solvent by adopting a one-pot method; the production cost is low; the operation is simple, and the method is suitable for industrial production.
Description
Technical Field
The scheme belongs to the technical field of pharmaceutical chemical industry, and particularly relates to a synthetic method of a terbutaline key intermediate 3, 5-dihydroxyacetophenone.
Background
Terbutaline (Terbutaline) was developed in 1966 by Kjell Wetterlin and Leiv Svensson of Astra, sweden. They substituted the isopropyl group of procaterol with tert-butyl. This increases the intensity and introduces a higher beta 2-adrenoreceptor selectivity in the lung compared to salbutamol. Potent β2-receptor agonists marketed by asteraneca (AstraZeneca) in the united kingdom. The composition is mainly used for dilating trachea and increasing pulmonary ventilation in clinic, and can be used for treating symptoms such as asthma, obstructive pneumonia, smooth muscle spasm, shock and the like. Terbutaline has the chemical name of 5- (1-hydroxy-2-tertiary butyl amino ethyl) benzene-1, 3-diphenol and the chemical structural formula as follows:
the patent with publication number CN105254512B discloses a preparation method of terbutaline sulfate, which comprises the following steps: (1) hydroxy protection: acetic anhydride is used as a hydroxyl protecting group, and 3, 5-diacetoxy acetophenone is prepared under the catalysis of a catalyst; (2) synthesis of α -bromo-3, 5-dihydroxyacetophenone: performing bromination reaction on the 3, 5-diacetoxy acetophenone, and then removing acetyl protection to obtain 2-bromo-1- (3, 5-dihydroxyphenyl) ethanone; (3) carbonyl reduction: intermediate 2-bromo-1- (3, 5-dihydroxyphenyl) ethanone is reduced to obtain intermediate 2-bromo-1- (3, 5-dihydroxyphenyl) ethanol; (4) synthesis of terbutaline sulfate: condensing 2-bromo-1- (3, 5-dihydroxyphenyl) ethanol with tert-butylamine, and salifying with sulfuric acid to obtain terbutaline sulfate.
The technical problems of high-risk operations such as high-pressure hydrogenation and high-risk reagents such as methyl lithium and azomethane and high cost existing in the existing terbutaline sulfate synthesis method are solved, 3, 5-dihydroxyacetophenone is adopted as a raw material, and terbutaline sulfate is obtained through hydroxy protection, bromination reaction, carbonyl reduction, condensation reaction and salification with sulfuric acid. The liquid bromine is adopted as a brominating reagent in the route, so that the production operation is extremely unsafe, and the generated product has more impurities and is difficult to remove, thus being not suitable for industrial production.
Disclosure of Invention
The scheme provides a synthetic method of terbutaline key intermediate 3, 5-dihydroxyacetophenone, which is suitable for industrial production.
In order to achieve the purpose, the scheme provides a synthetic method of a terbutaline key intermediate 3, 5-dihydroxyacetophenone, which comprises the following steps: the method comprises the following steps:
step S10, taking 3, 5-dihydroxybenzoic acid SM as a raw material, synchronously carrying out methylation and methyl esterification reaction with dimethyl sulfate under alkaline conditions, and carrying out aftertreatment to obtain a compound methyl 3, 5-dimethoxybenzoate;
step S20, carrying out condensation reaction on the compound 3, 5-dimethoxy methyl benzoate and methyl acetate under the action of strong alkali hydrogen drawing to obtain the compound 3- (3, 5-dimethoxy phenyl) -3-oxypropionic acid methyl ester;
step S30, under the strong acid condition, the compound 3- (3, 5-dimethoxy phenyl) -3-oxypropionic acid methyl ester synchronously carries out hydrolysis decarboxylation reaction and demethylation reaction at high temperature by a one-pot method, and then the high-purity compound 3, 5-dihydroxyacetophenone is obtained by solvent crystallization and impurity removal, wherein the reaction route is as follows:
the beneficial effect of this scheme: dangerous format reactions are effectively avoided; the hydrolysis decarboxylation and the demethylation are more favorable for synchronously recycling the solvent by adopting a one-pot method; the reaction condition of the whole route is mild, the equipment requirement is low, and the production cost is low; the operation is simple, and the method is suitable for industrial production.
Further, in the step S10, the reaction solvent is one or more of water, toluene, ethylbenzene and xylene.
Further, in the step S10, the reaction solvent is a mixture of water and toluene.
Further, in the step S10, the alkaline substance is one or more of sodium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, and potassium carbonate.
Further, in the step S10, the alkaline substance is a mixed alkali of sodium hydroxide and sodium bicarbonate.
Further, in the step S10, the methyl ether reagent is one of dimethyl sulfate, dimethyl carbonate, and methyl iodide.
Further, in the step S10, the methyl ether reagent is preferably dimethyl sulfate.
Further, in the step S20, the reaction solvent is one of methanol, ethanol, methyl acetate and tetrahydrofuran.
Further, in the step S20, the reaction solvent is methyl acetate.
Further, in the step S20, the strong base is one of sodium methoxide, sodium ethoxide, sodium tert-butoxide, liHMDS, naHMDS, and sodium amide.
Further, in the step S20, the strong base is sodium methoxide.
Further, in the step S30, the strong acid is one of concentrated hydrochloric acid, hydrobromic acid and concentrated sulfuric acid.
Further, in the step S30, the strong acid is concentrated hydrochloric acid
Further, in the step S30, the high temperature reaction temperature is 60 to 100 ℃.
Further, in the step S30, the high temperature reaction temperature is preferably 85 to 90 ℃.
Further, the crystallization solvent is a single solvent system or a mixed solvent system, wherein the single solvent system is one of ethanol, isopropanol, toluene, methyl tertiary butyl ether and acetone, and the mixed solvent system is any one of methanol/water, ethanol/water, isopropanol/water, acetone/water, ethyl acetate/n-heptane, isopropyl acetate/n-heptane and toluene/methyl tertiary butyl ether.
Further, the crystallization solvent is an ethanol/water system.
Drawings
Fig. 1 is a schematic flow chart of embodiment 1 of the present invention.
FIG. 2 is an HPLC chart of methyl 3, 5-dimethoxybenzoate of example 1 of the present invention.
FIG. 3 is an HPLC chart of methyl 3- (3, 5-dimethoxyphenyl) -3-oxopropionate according to example 1 of the present invention.
FIG. 4 is an HPLC chart of 3, 5-dihydroxyacetophenone of example 1 of the present invention.
Fig. 5 is a schematic structural diagram of embodiment 2 of the present invention.
Detailed Description
The following is a further detailed description of the embodiments:
the labels in the drawings of this specification include: 1. a bottle body; 2. a housing; 3. a first bottle mouth; 4. a second bottle mouth; 5. a third bottle mouth; 6. an ingress pipe; 7. a delivery tube; 8. a bracket; 9. a water outlet pipe; 10. a valve knob; 11. a vertical axis; 12. a fan blade; 13. a pull rope; 14. rubber balls; 15. and (3) a torsion spring.
Example 1 is substantially as shown in figures 1-4:
a synthetic method of terbutaline key intermediate 3, 5-dihydroxyacetophenone comprises the following steps: the method comprises the following steps:
step S10, adding 154.1g of 3, 5-dihydroxybenzoic acid, 84g of sodium hydroxide and 308g of water into a reaction bottle, uniformly stirring, then dropwise adding 264.6g of dimethyl sulfate, and reacting for 8 hours until the reaction is complete; 92.4g of sodium bicarbonate and 138.6g of dimethyl sulfate are added into the reaction solution, and the reaction is carried out for 4 hours at normal temperature until the reaction is complete after the completion of the dropwise addition. 308g of dichloromethane is added into the reaction solution, the mixture is stirred, then the mixture is kept stand for layering, 154g of dichloromethane is added into a water layer for extraction, the organic layers are combined, washed once, the organic layers are concentrated to dryness under reduced pressure, 462g of n-heptane is added for pulping, filtering and drying under reduced pressure at 40 ℃ are carried out, and the compound 3, 5-dimethoxy methyl benzoate is obtained: 179.1g, molar yield: 91.3%.
Step S20, adding 98.1g of compound methyl 3, 5-dimethoxy benzoate, 74g of methyl acetate into a reaction bottle, uniformly stirring, and adding 37.8g of sodium methoxide in batches at normal temperature; after the addition, the temperature is raised, the reflux reaction is carried out for 4 to 6 hours, 294g of dichloromethane is added after the reaction is completed, and stirring and dispersion are carried out. Cooling the reaction liquid to 0-5 ℃, slowly dropwise adding dilute hydrochloric acid to adjust the pH value to be nearly neutral, standing for layering, adding 196g of dichloromethane into a water layer for extraction, combining organic layers, washing once, and concentrating the organic layers to dryness to obtain a light yellow oily substance, namely the compound 3- (3, 5-dimethoxy phenyl) -3-oxypropionic acid methyl ester: 111.0g, molar yield: 93.3%.
Step S30, adding 111.0g of the obtained compound methyl 3- (3, 5-dimethoxy phenyl) -3-oxopropionate into a reaction bottle, adding 333g of concentrated hydrochloric acid, heating and refluxing for reaction for 4 hours, adding 111g of concentrated hydrochloric acid, and continuing to react for 4 hours until the reaction is complete. Cooled to room temperature, extracted with 444g of dichloromethane and 222g of dichloromethane in sequence, the organic layers were combined and washed with half-saturated sodium bicarbonate solution, saturated sodium chloride solution and water in sequence. The organic layer is obtained, concentrated to dryness under reduced pressure, added with a small amount of ethanol to carry out drying, added with 555g of 40% ethanol aqueous solution for recrystallization, cooled to 0-5 ℃ and stirred for crystallization for 3-4 hours, filtered, and the obtained solid is dried to constant weight under reduced pressure and 50 ℃. Obtaining a pale yellow solid which is the compound 3, 5-dihydroxyacetophenone: 58.5g, molar yield 82.5%.
Example 2, as shown in fig. 5:
the embodiment is different from the embodiment 1 in that the reaction bottle is a three-mouth bottle, the three-mouth bottle comprises a bottle body 1 and a shell 2, a first bottle mouth 3, a second bottle mouth 4 and a third bottle mouth 5 are arranged on the upper side of the bottle body 1, the first bottle mouth 3, the second bottle mouth 4 and the third bottle mouth 5 are vertically upwards arranged, the shell 2 is sleeved outside the bottle body 1, an ingress pipe 6 and an egress pipe 7 are arranged on the shell 2, the shell 2 and the bottle body 1 enclose to form a cavity, the ingress pipe 6 and the egress pipe 7 are communicated with the cavity, the matching part of the shell 2 and the three-mouth bottle is made of elastic materials, a bracket 8 is connected on the shell 2, a water outlet pipe 9 penetrating out of the shell 2 is communicated at the bottom of the bottle body 1, a valve button 10 playing a role of on-off is matched on the water outlet pipe 9, a vertical shaft 11 is fixedly arranged in the shell 2, a ball screw is arranged on the vertical shaft 11, nuts matched with the ball screw, fan blades 12 and pull ropes 13 are fixedly connected on the nuts, the fan blades 12 are matched with the lead-in shafts, the fan blades 12 are sleeved with the torsion springs 15, the lower ends of the shell 2 are fixedly connected with the fan blades 12, the torsion springs 15,
when the bottle is used, when ingredients in the bottle 1 need to be heated or cooled, hot steam or cold air is led in through the leading-in pipe 6, the hot steam or the cold air directly faces the fan blades 12, the fan blades 12 rotate positively to drive the pull ropes 13 to rotate, then the rubber balls 14 impact the bottle 1, the bottle 1 shakes, liquid in the bottle 1 shakes, the liquid in the bottle 1 is heated uniformly, if the bottle 1 is not shaken, only the periphery of the bottle 1 is heated, then the liquid contacted with the periphery of the bottle 1 is heated quickly, the liquid in the middle of the bottle 1 is heated slowly, and the reaction is slow. The rubber ball 14 is provided with a cavity, so that the bottle body 1 cannot be crashed. Hot steam or cold air is discharged from the delivery tube 7.
At the same time, the fan blade 12 rotates forward to drive the nut to rotate forward, the nut moves upward, the torsion spring 15 receives torsion force, and then
When the nut moves up, the fan blade 12 is staggered with the inlet of the ingress pipe 6, the fan blade 12 is not pushed by water vapor at this time, and the torsion spring 15 is deformed again, so that the nut drives the fan blade 12 to rotate reversely, the pull rope 13 rotates reversely at this time, and the rubber ball 14 impacts the bottle body 1 again. The rubber ball 14 positively or reversely impacts the bottle body 1, so that the bottle body 1 is rocked, the solution in the bottle body 1 is stirred, the reaction speed of the solution is accelerated, the fan blades 12 move up and down, the rubber ball 14 impacts different parts of the bottle body 1, and the bottle body 1 is prevented from being broken due to the fact that the rubber ball 14 impacts the same place.
After heating or cooling, and after the liquid in the bottle body 1 is reacted completely, the valve button 10 is opened to directly guide out the liquid, so that the common phenomenon that the liquid ingredients flow onto the outer wall along the bottle mouth of the three-mouth bottle can not occur, and the use is cleaner and convenient.
The foregoing is merely exemplary embodiments of the present invention, and specific structures and features that are well known in the art are not described in detail herein. It should be noted that modifications and improvements can be made by those skilled in the art without departing from the structure of the present invention, and these should also be considered as the scope of the present invention, which does not affect the effect of the implementation of the present invention and the utility of the patent. The protection scope of the present application shall be subject to the content of the claims, and the description of the specific embodiments and the like in the specification can be used for explaining the content of the claims.
Claims (10)
1. A synthetic method of terbutaline key intermediate 3, 5-dihydroxyacetophenone is characterized in that: the method comprises the following steps:
step S10, taking 3, 5-dihydroxybenzoic acid SM as a raw material, synchronously carrying out methylation and methyl esterification reaction with dimethyl sulfate under alkaline conditions, and carrying out aftertreatment to obtain a compound methyl 3, 5-dimethoxybenzoate;
step S20, carrying out condensation reaction on the compound 3, 5-dimethoxy methyl benzoate and methyl acetate under the action of strong alkali hydrogen drawing to obtain the compound 3- (3, 5-dimethoxy phenyl) -3-oxypropionic acid methyl ester;
step S30, under the strong acid condition, the compound 3- (3, 5-dimethoxy phenyl) -3-oxypropionic acid methyl ester synchronously carries out hydrolysis decarboxylation reaction and demethylation reaction at high temperature by a one-pot method, and then the high-purity compound 3, 5-dihydroxyacetophenone is obtained by solvent crystallization and impurity removal, wherein the reaction route is as follows:
。
2. the method for synthesizing terbutaline key intermediate 3, 5-dihydroxyacetophenone according to claim 1, which is characterized in that: in the step S10, the reaction solvent is one or more of water, toluene, ethylbenzene and xylene.
3. The method for synthesizing terbutaline key intermediate 3, 5-dihydroxyacetophenone according to claim 1, which is characterized in that: in the step S10, the alkaline substance is one or more of sodium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate and potassium carbonate.
4. The method for synthesizing terbutaline key intermediate 3, 5-dihydroxyacetophenone according to claim 1, which is characterized in that: in the step S10, the methyl ether reagent is one of dimethyl sulfate, dimethyl carbonate and methyl iodide.
5. The method for synthesizing terbutaline key intermediate 3, 5-dihydroxyacetophenone according to claim 1, which is characterized in that: in the step S20, the reaction solvent is one of methanol, ethanol, methyl acetate and tetrahydrofuran.
6. The method for synthesizing terbutaline key intermediate 3, 5-dihydroxyacetophenone according to claim 5, which is characterized in that: in the step S20, the reaction solvent is methyl acetate.
7. The method for synthesizing terbutaline key intermediate 3, 5-dihydroxyacetophenone according to claim 1, which is characterized in that: in the step S20, the strong base is one of sodium methoxide, sodium ethoxide, sodium tert-butoxide, liHMDS, naHMDS and sodium amide.
8. The method for synthesizing terbutaline key intermediate 3, 5-dihydroxyacetophenone according to claim 1, which is characterized in that: in the step S30, the strong acid is one of concentrated hydrochloric acid, hydrobromic acid and concentrated sulfuric acid.
9. The method for synthesizing terbutaline key intermediate 3, 5-dihydroxyacetophenone according to claim 1, which is characterized in that: in the step S30, the high-temperature reaction temperature is 60-100 ℃.
10. The method for synthesizing terbutaline key intermediate 3, 5-dihydroxyacetophenone according to claim 1, which is characterized in that: the crystallization solvent is a single solvent system or a mixed solvent system, wherein the single solvent system is one of ethanol, isopropanol, toluene, methyl tertiary butyl ether and acetone, and the mixed solvent system is any one of methanol/water, ethanol/water, isopropanol/water, acetone/water, ethyl acetate/n-heptane, isopropyl acetate/n-heptane and toluene/methyl tertiary butyl ether.
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| CN117550981A (en) * | 2024-01-12 | 2024-02-13 | 成都工业学院 | Preparation method of 2-amino-5-fluoro acetophenone |
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